Tricyclic Enone Research Articles

Desymmetrization of Cyclohexadienones via [3+2]/[2+1] Domino Annulation: Access to Cyclopropane Fused Tricyclic Enones

AbstractA [3+2]/[2+1] domino annulation reaction of cyclohexadienones and α‐aryl vinylsulfonium salts has been reported. A range of cyclopropane fused tricyclic enones bearing four contiguous stereocenters were obtained as a single diastereomer in 44–93% yields. The synthetic utility was demonstrated with the gram‐scale reactions and further transformations of the products.

Concise Synthesis of 11-Noriridoids via Pauson-Khand Reaction.

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.

AlCl3‐Promoted Conia‐Ene‐Related Cyclization of α,ω‐Diethylenic Ketones and 1,2‐ or 1,3‐Hydroalkenylation of Unactivated Cyclopropanes

Abstractα,β‐Unsaturated enones possessing an unactivated olefin at the ϵ‐, ζ‐ or η‐position underwent an aluminum chloride‐promoted Conia‐ene‐related cyclization, affording unsaturated decalones or hexahydroindenones in generally good yields. Cyclopropanes could be used as olefin surrogates in this process, leading to the same bicyclic products in slightly improved efficiency as the result of 1,2‐ or 1,3‐hydroalkenylation reactions. This method provided an access to a whole range of bi‐ or tricyclic enone synthons, some of which were potentially useful as odorants or in the synthesis of biologically active molecules.

Synthetic Studies to exo‐Ring‐Junction based Fused 5/5/n‐Tricyclic Systems: Access to A, B, C‐Ring System of Longeracinphyllin A, Himalenine D, and Daphnipaxiamine A.

AbstractWe report a short synthetic approach to various tricyclic systems that are present in several diquinane‐based natural products starting with a readily available exo‐dicyclopentadiene‐1‐one. To this end, we have successfully assembled a fused 5/5/7‐tricyclic enone via ring‐rearrangement metathesis as a key step. The strategy has been further extended to synthesize the 1,3‐dihydroxy and then 1‐keto‐3‐hydroxy derivatives by utilizing regio‐ and stereoselective epoxidation and ring‐rearrangement metathesis reactions as key steps. All these target compounds are found to be present in diquinane‐based natural products such as longeracinphyllins A, himalenine D and daphnipaxianine A, etc. Moreover, the newly synthesized tricyclic compounds matches the exact ring‐junction stereochemistry (5/5‐exo) of these natural products. Hence, the synthetic studies disclosed here may be useful in the synthesis of biologically significant natural products and in the drug design. The newly synthesized molecules were characterized by NMR and HRMS data. Some of these structures were confirmed by a single crystal X‐ray diffraction studies.

Design and Synthesis of Linearly Fused Triquinanes through Tandem‐Metathesis: Access to Basic Core of Cucumin, Capnellene, Chondrosterin, and Xeromphalinone

AbstractHerein, a short synthetic approach to linearly fused tricyclic enone 1 and cis‐anti‐cis type hydroxy‐triquinane 2 has been described in an efficient manner by employing tandem‐metathesis as a key step. The triquinane‐based enone 1 is prepared by a Babler–Dauben oxidation of hydroxy‐triquinane 2, which is assembled by following a three‐step sequence involving a regio‐ and stereoselective allylation, vinyl Grignard addition, and tandem‐metathesis. Our strategy relies on exo‐tricyclic ketone, which is derived from readily available exo‐dicyclopentadiene‐1‐one. The newly synthesized molecules were identified and characterized by nuclear magnetic resonance spectroscopy (NMR), and high‐resolution mass spectrometry (HRMS) data. It is worth mentioning that tricyclic enone 1 is present as a core unit of many naturally occurring polyquinanes, particularly xeromphalinone family members. Hence, our approach may be useful in the synthesis of such bioactive molecules.

Total Synthesis of (-)-Antroalbocin A Enabled by a Strain Release-Controlled Photochemical 1,3-Acyl Shift.

The first bioinspired, enantioselective, and protecting group free total synthesis of the antibacterial sesquiterpenoid (-)-antroalbocin A (1) has been achieved in 12 steps (5.4% overall yield) from dimedone. An organocatalytic Robinson annulation gave rapid access to the tricyclic enone (19) as starting material for the photochemical domino process of deconjugation and sigmatropic 1,3-acyl shift. Computational data of this process indicate that the 1,3-acyl shift benefits from the highly strained 1,3-enone 8. The transformation of 8 to its bridged isomer 5 is exergonic and, therefore, enables an increased conversion compared to unstrained substrates.

Silver(I)-Catalyzed Oxidative Intramolecular Cyclopropanation: Access to Complex Tricyclo[3.3.1.0]nonanediones via Semipinacol-Type Rearrangement.

An unconventional Ag(I)-catalyzed intramolecular cyclopropanation of prochiral alkyne-tethered cyclohexadienones has been developed using simple perchloric acid as an external oxidant. The transformation involves the formation of a perchloryloxy vinyl-silver species, which then proceeds through either intramolecular conjugate addition or an α-oxo silver carbene pathway to yield cyclopropane fused tricyclic enones with high diastereoselectivity. In the case of C-tethered cyclohexadienones, the reaction proceeds further via acid mediated semipinacol-type rearrangement to give complex and highly strained tricyclo[3.3.1.0]nonanediones. This cascade annulation has wide functional-group tolerance and broad substrate scope. Late-stage functionalization of estrone was also demonstrated with excellent diastereoselectivity.

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

AbstractThe first enantioselective total synthesis of (−)‐cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh2(S‐TBPTTL)4, and the enone 1,2‐addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain‐promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (−)‐1 was completed by a late‐stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.

Eight-Step Enantioselective Total Synthesis of (-)-Cycloclavine.

The first enantioselective total synthesis of (-)-cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh2 (S-TBPTTL)4 , and the enone 1,2-addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain-promoted Diels-Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (-)-1 was completed by a late-stage intramolecular Diels-Alder furan (IMDAF) cycloaddition to install the indole.

Suberosanes as Potential Antitumor Agents: First Enantioselective Total Synthesis of (1S)-Suberosanone and Configurational Assignment of Suberosenol A

The first enantioselective total syntheses of two marine sesquiterpenes, natural (1<i>S</i>)-suberosanone and (1<i>S</i>)-suberosenol A, are achieved leading to the assignment of the absolute configuration of natural suberosenol A. A new access to (1<i>S</i>)-suberosenone from a key tricyclic enone was also developed leading to an overall improvement of the synthesis, allowing an efficient route to suberosenol A. Hyperbaric asymmetric Michael addition and a highly efficient silver trifluoroacetate mediated α-alkylation for the formation of ring A completed the key steps of the synthesis. Regrettably, synthetic (1<i>S</i>)-suberosanone did not retain the reported picomolar cytotoxic activity displayed by the natural product, the reason for which remains to be elucidated.

Asymmetric allylation of ketones and subsequent tandem reactions catalyzed by a novel polymer-supported titanium-BINOLate complex.

By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL = 1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson-Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co2(CO)8/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.

Divergent synthesis of pseudoenantiomers for ABC-ring moiety of steroids

Steroid family has various bioactivities and characteristic polycyclic structure. Although several synthetic methods have been reported, more efficient way is desired for medicinal chemistry. In this Letter, we synthesized pseudoenantiomers of tricyclic enones toward both enantiomers for ABC-ring moiety of steroids utilizing d-mannitol as a chiral source. The key steps are radical domino cyclization of polyalkenyl-β-keto ester into tricyclic keto ester and subsequent dealkoxycarbonylation.

Divergent Total Synthesis of Indoxamycins A, C, and F

The concise and divergent total synthesis of (−)-indoxamycins A, C, and F has been completed for the first time by using a tricyclic enone as the common late-stage intermediate. The key steps of the strategy are based on an Ireland–Claisen rearrangement, a stereodivergent reductive 1,6-enyne cyclization, and a tandem 1,2-addition/oxa-Michael/methylenation reaction.

Synthesis of (±)-14-epi-hydroxydolasta-1(15),7,9-triene and (±)-7-epi-acetoxy-14-epi-hydroxydolasta-1(15),8-diene*Taken in part from the Ph.D. dissertation of Jianhua Yu, University of Georgia, Athens, Georgia, USA, 2009.

1,3-Dimethyl-2-nitrobenzene was converted to the key intramolecular Friedel–Crafts intermediate 24 in ten steps. Treatment of 24 with TiCl4 produced tricyclic enone 25 in 61%–75% yield, having the requisite trans relationship of the two angular methyl groups and many of the salient features of the dolastane diterpenes. The structure of enone 25 was verified by X-ray crystallography analysis. Cyclization product 25 permitted the facile synthesis of (±)-14-epi-hydroxydolasta-1(15),7,9-triene and (±)-7-epi-acetoxy-14-epi-hydroxydolasta-1(15),8-diene, which are detailed in this article.

ChemInform Abstract: Fully Regiocontrolled Synthesis of Deacetamidoisocolchicine: Formal Total Synthesis of Colchicine.

A 19-step synthesis of deacetamidoisocolchicine 4 has been developed starting from commercially available benzaldehyde 10. Key elements of the strategy used include Robinson annulation of the benzosuberone 15 to produce the tricyclic enone 18 and elaboration of this latter compound to the tetracyclic α-methoxy enone 7a. Base-promoted ring-expansion of 7a then provided the title compound 4, the acquisition of which constitutes a formal total synthesis of the alkaloid colchicine 1. In connection with efforts to optimise the yield of 4, the novel acid-catalysed conversion of 32 into dibenzocyclooctene 35 has been observed. The X-ray crystal structures of compound 35 and the novel dichlorocarbene insertion product 24 are reported.

ChemInform Abstract: Synthetic Studies on Diterpenoid Quinones with Interleukin-1 Inhibitory Activity. Total Synthesis of (.+-.)- and (+)-Triptoquinone A.

An efficient first total synthesis of (±)- and (+)-triptoquinone A (1), a novel diterpenoid quinone with significant inhibitory activity against interleukin-1 releases, has been completed. Birch reduction of tricyclic enone (±)-7, prepared from known 6-methoxy-2-isopropyl-1-naphthol (22), which is readily available in large quantities, was followed by immediate enolate trapping to provide silyl enol ether (±)-30. Compound 30 was converted into carboxylic acid (±)-4 via the corresponding enol triflate (±)-31 either by sequential palladium-catalyzed carbonylation and oxidation or by direct carboxylation. The total synthesis of (±)-1 was completed by oxidation of (±)-4 with CAN in 12 steps from 22 in 19% overall yield at best. A second, enantioselective total synthesis of (+)-1 was accomplished via (+)-7, which was prepared by (-)-N-[4-(trifluoromethyl)benzyl]cinchonidium bromide(33) catalyzed asymmetric Michael reaction of 6 with ethyl vinyl ketone and a subsequent aldol condensation

Isolation, enzyme-bound structure and antibacterial activity of platencin A 1 from Streptomyces platensis

Natural products continue to serve as one of the best sources for discovery of antibacterial agents as exemplified by the recent discoveries of platensimycin and platencin. Chemical modifications as well as discovery of congeners are the main sources for gaining knowledge of structure–activity relationship of natural products. Screening for congeners in the extracts of the fermentation broths of Streptomyces platensis led to the isolation of platencin A 1, a hydroxy congener of platencin. The hydroxylation of the tricyclic enone moiety negatively affected the antibacterial activity and appears to be consistent with the hydrophobic binding pocket of the FabF. Isolation, structure, enzyme-bound structure and activity of platencin A 1 and two other congeners have been described.

Efficient Horner–Wadsworth–Emmons intramolecular cyclisation of a N-substituted phthalimide promoted by KF-Alumina: a general tool for the synthesis of functionalised isoindolinones

An intramolecular Horner–Wadsworth–Emmons reaction promoted by KF-Alumina involving a N-substituted phthalimide, cleanly and efficiently furnishes an interesting α,β-unsaturated tricyclic enone which may undergo selective alkylations at the α′-position.

Synthesis of the AB subunit of angelmicin B through a tandem alkoxy radical fragmentation-etherification sequence.

The synthesis of the tricyclic enone 2, corresponding to the AB subunit of the novel tyrosine kinase inhibitor angelmicin B, is described. The strategy centers on an intramolecular Diels-Alder (IMDA) reaction on triene 4 to provide the complex decalin 3, which is elaborated to 2. Other key steps are the formation of the THF ring in 2 through a tandem alkoxy radical fragmentation-etherification on the lactol derived from 3, and the synthesis of 4 via a ring-closing ene-yne metathesis (RCEYM).

Construction of Tricyclic Enone, a Common Precursor for Aphidicolane and Stemodane B/C/D‐Ring System.

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