Total Synthesis of the Hypermodified RNA Bases Wybutosine and Hydroxywybutosine and Their Quantification Together with Other Modified RNA Bases in Plant Materials

We report an efficient synthesis of the hypermodified natural tRNA modifications wybutosine (yW) and hydroxywybutosine (OHyW). We also describe the preparation of isotopically labeled analogues for precise quantification of yW and OHyW in different tissues including plant materials. The synthesis involved the formation of the unusual tricyclic ring structure of the bases by using a catalytic, intramolecular hydroamination reaction. The basis for the synthesis is also a stereoselective coupling reaction that allows the introduction of the fully substituted side chains to the tricyclic core structure. The isotopologues of yW and OHyW, together with other isotopically labeled tRNA modifications, were ultimately used in LC‐MS quantification experiments to investigate the role of the modified bases in the translational process. Quantification was performed in the plant species Arabidopsis thaliana.     

Total synthesis of (+/-)-taiwaniaquinol B via a domino intramolecular friedel-crafts acylation/carbonyl alpha-tert-alkylation reaction

The first synthesis of taiwaniaquinol B, a 6-nor-5(6-->7)abeoabietane-type diterpenoid exhibiting the uncommon fused 6-5-6 tricyclic carbon skeleton, was accomplished in 15 steps. A Lewis acid-promoted tandem intramolecular Friedel-Crafts/carbonyl alpha-tert-alkylation reaction was exploited as the core strategy for the synthesis of the sterically congested 1-indanone-containing tricyclic structure. This multiple carbon-carbon bond forming reaction exploits the unique reactivity of Meldrum's acid. The facile precursor synthesis makes this a useful methodology for the expedient modification and assembly of sterically congested 1-indanone-containing ring systems.     

Facile Synthesis of Tricyclic 1,2,4-Oxadiazolines-Fused Tetrahydro-Isoquinolines from Oxime Chlorides with 3,4-Dihydroisoquinoline Imines

A mild and efficient strategy for the synthesis of tricyclic 1,2,4-oxadiazolines-fused tetrahydro-isoquinolines derivatives via [3 + 2] cycloaddition reaction is reported. The reactions provided the functionalized tricyclic 1,2,4-oxadiazolines in high yields (up to 96%). This protocol is simple and easy to handle. Moreover, a gram-scale experiment further highlights the synthetic utility. The chemical structure of the product was determined by X-ray single-crystal structure analysis. A possible mechanism for this transformation is proposed to explain the reaction process.     

Highly diastereoselective approach toward (+/-)-tetraponerine T6 and analogues via the double cycloisomerization-reduction of bis-alkynylpyrimidines

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization-reduction of bis-alkynylpyrimidines 3a-m, has been developed. The requisite bis-alkynylpyrimidines 3a-m were readily prepared via regioselective sequential Sonogashira coupling reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a-m were converted into the 5-6-5 tricyclic heteroaromatic cores 4a-m via the Cu(I)-assisted double cycloisomerization reaction. The reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis. Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO2-catalyzed hydrogenation of bis-pyrrolopyrimidines 4d, 4g, and 4i in acidic media afforded stable amidinium derivatives, 11a, 11b, and 11c. Further reduction of the latter with LiAlH4 allowed for the highly diastereoselective total synthesis of (+/-)-tetraponerine T6 and its analogues.     

Synthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists

The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.     

Asymmetric synthesis of the core structure of leucosceptroids A-D

The asymmetric synthesis of the core structure of leucosceptroids A-D has been achieved. The key steps of the synthesis includes the formation of the cis-2,5-disubstituted THF ring by TPAP catalytic oxidative cyclization followed by a highly diastereoselective intramolecular Diels-Alder reaction to fashion the fused tricyclic hydrindane ring system.     

Total synthesis of batzelladine D

[structure: see text] Stereoselective total synthesis of batzelladine D was accomplished in 15 steps. This synthesis features (i) successive 1,3-dipolar cycloaddition reactions to form the 2,5-disubstituted pyrrolidine ring system, (ii) esterification of the side chain to the bicyclic guanidine carboxylate, a common synthetic intermediate of batzelladine alkaloids, and (iii) tricyclic guanidine formation under the Mitsunobu reaction conditions.     

Unique strategy for the assembly of the carbon skeleton of guanacastepene A using an allenic Pauson-Khand-type reaction

[reaction: see text] An approach to the highly functionalized tricyclic core of guanacastepene A has been developed using a rhodium(I)-catalyzed allenic Pauson-Khand reaction. This approach constitutes a conceptually novel strategy for the synthesis of this tricyclic framework, whereby the six-membered ring is formed intially followed by simultaneous formation of the five- and seven-membered rings.     

Synthesis of the unique angular tricyclic chromone structure proposed for aspergillitine, and its relationship with alkaloid TMC-120B

The synthesis of the tricyclic angular chromone structure originally assigned to aspergillitine is reported. The synthesis was achieved in 11 steps and 15% overall yield from 2,4-dihydroxypropiophenone, through the intermediacy of 2,3-dimethyl-7-hydroxychromen-4-one. Construction of the nitrogen-bearing heterocyclic ring entailed a Stille cross-coupling reaction with n-Bu(3)SnCH(2)CH=CH(2), followed by double bond isomerization, oximation of the chromone carbonyl, and a final microwave-assisted electrocyclization of the thus formed 6π-electron aza-triene system.     

Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction

Herein we target the total synthesis of 2-epi-α-cedren-3-one, a natural compound isolated from the essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and robust series of chemical transformations, with prominent features including a low temperature and highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the target molecule. Our optimum cyclisation protocol utilises only 20?mol% of transition metal, and delivers the complex tricyclic structure in just 10?min. Further manipulations of the annulation product culminate in the first total synthesis of the described natural target.     

Total Synthesis of Homodimericin A

We report the concise total synthesis of homodimericin A ( 1 ), a recently identified fungal metabolite bearing an unprecedented molecular architecture. The success of the approach hinges on a series of rationally designed and bioinspired transformations, including a Moore rearrangement to assemble the monomeric hydroquinone precursor, homodimerization through double Michael addition to construct the planar A/B/C tricyclic framework, and a tandem Diels–Alder reaction/carbonyl–ene cyclization to forge the congested D/E/F tricyclic cage motif. Unequivocal evidence for the elucidated structure of homodimericin A was also provided by this study.     

Total Synthesis of Homodimericin A

We report the concise total synthesis of homodimericin A ( 1 ), a recently identified fungal metabolite bearing an unprecedented molecular architecture. The success of the approach hinges on a series of rationally designed and bioinspired transformations, including a Moore rearrangement to assemble the monomeric hydroquinone precursor, homodimerization through double Michael addition to construct the planar A/B/C tricyclic framework, and a tandem Diels–Alder reaction/carbonyl–ene cyclization to forge the congested D/E/F tricyclic cage motif. Unequivocal evidence for the elucidated structure of homodimericin A was also provided by this study.     

Enantiospecific approach to the tricyclic core structure of tricycloillicinone, ialibinones, and takaneones via ring-closing metathesis reaction

Enantiospecific synthesis of the tricyclic core structure present in the biologically active natural products tricycloillicinone, ialibinones, and takaneones, starting from the readily available campholenaldehyde employing a transannular RCM reaction as the key step, has been accomplished.     

Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors

Flavones such as chrysin show structural similarities to androgens, the substrates of human aromatase, which converts androgens to estrogens. Aromatase is a key target in the treatment of hormone-dependent tumors, including breast cancer. Flavone-based aromatase inhibitors are of growing interest, and chrysin in particular provides a (natural) lead structure. This paper reports multicomponent synthesis as a means for facile modification of the chrysin core structure in order to add functional elements. A Mannich-type reaction was used to synthesize a range of mono- and disubstituted chrysin derivatives, some of which are more effective aromatase inhibitors than the benchmark compound, aminoglutethimide. Similarly, the reaction of chrysin with various isonitriles and acetylene dicarboxylates results in a new class of flavone derivatives, tricyclic pyrano-flavones which also inhibit human aromatase. Multicomponent reactions involving flavones therefore enable the synthesis of a variety of derivatives, some of which may be useful as anticancer agents.     

Synthesis of the tricyclic core of vinigrol via an intramolecular Diels-Alder reaction

[reaction: see text] Herein, we present a successful synthesis of the tricyclic core of vinigrol (1). Our approach takes advantage of a highly regioselective intramolecular Diels-Alder reaction of the diene 11 to construct two rings of the tricyclic vinigrol skeleton 12.     

Enantiocontrolled synthesis of jasmonates via tandem retro-Diels-Alder-ene reaction activated by a silyl substituent

[reaction: see text] An enantiocontrolled synthesis of (-)-methyl 6-epi-cucurbate and (+)-methyl jasmonate was established from a chiral tricyclic lactone via a new type of tandem retro-Diels-Alder-ene reaction activated by a trimethysilyl substituent as the key step.     

A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach

Hydroxyindoline-derived scaffold, 9, was synthesized with the goal of generating a library of indoline-based natural product-like tricyclic derivatives to be utilized as small-molecule chemical probes. The tricyclic ring was obtained by a Mitsunobu reaction of the N-nosyl amino acid conjugate with the primary hydroxyl group. The solid-phase synthesis was achieved by immobilizing scaffold 9 onto the solid support giving a compound, 15. This was then subjected to a series of reactions on solid phase, including the Mitsunobu reaction, leading to the desired indoline-derived tricyclic derivative. The final product has two diversity sites: (i) amino acid as the first diversity and (ii) amidation of the secondary amine for the second diversity. These two diversity sites were utilized in the library generation by IRORI split-and-mix approach.     

Scope of the radical addition-cyclization-elimination reaction of oxime ether towards the synthesis of tricyclic lactam derivatives

The synthesis of tricyclic lactam building blocks by the radical addition-cyclization-elimination (RACE) reaction is presented. A range of oxime ethers carrying unsaturated ester part have been tested for the radical reaction. A variety of substituents were incorporated around the aromatic backbones and their effect on the RACE reaction has been examined. In addition, the power of RACE reaction is demonstrated by preparation of a key intermediate for the synthesis of constrained analogue of methoctramine.     

Revisiting a classic approach to the Aspidosperma alkaloids: an intramolecular Schmidt reaction mediated synthesis of (+)-aspidospermidine

[reaction: see text] A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation sequence, a selective "redox ketalization", and an intramolecular Schmidt reaction. A Fischer indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and Dolfini in their classic aspidospermine synthesis.     

Enantiospecific synthesis of the proposed structure of the antitubercular marine diterpenoid pseudopteroxazole: revision of stereochemistry.

An enantiospecific synthesis of structure 1, previously assigned to the antitubercular marine natural product pseudopteroxazole, has been accomplished as outlined in Scheme 1. Coupling of diene acid 3 and amino phenol 4 produced the amide 5, which was subjected to a novel oxidative intramolecular Diels-Alder reaction to generate the tricyclic lactam 6a stereoselectively. This product was transformed via intermediates 7-11 into the diene 13. Cationic cyclization of 13 afforded two diastereomeric tricyclic amphilectanes which were separated and transformed by parallel four-step sequences into 1 and 2, respectively. Neither 1 nor 2 were identical with pseudopteroxazole, indicating a need for revision of the structure, probably to 16.